Skip to Content
Translational Research Program (TRP)
Contact CIP
Show menu
Search this site
Last Updated: 10/10/18

SPORE in Neuroendocrine Tumors

University of Iowa

Principal Investigator:
M. Sue O’Dorisio, MD, PhD

Principal Investigator Contact Information

M. Sue O’Dorisio MD, PhD
RJ and LA Carver College of Medicine
Division of Pediatric Hematology/Oncology
University of Iowa Hospitals & Clinics
200 Hawkins Drive, 2524 JCP
Iowa City, IA 52242
Tel: (319) 356-3595
Fax: (319) 356-7659
Email: sue-odorisio@uiowa.edu

OVERALL ABSTRACT

The University of Iowa Neuroendocrine Tumor Specialized Program of Research Excellence (SPORE) is the first and only SPORE grant to fund research on Neuroendocrine tumors.

The Neuroendocrine Tumor SPORE (NET SPORE) includes four major projects and four cores that will explore the genetics of these tumors, their molecular makeup, and how this information can be used to develop new approaches to diagnosis and treatment. The main projects are:

Project 1: Theranostics In Neuroendocrine Tumors
Menda Yusuf, MD, Project Leader; M Sue O’Dorisio, MD, PhD, Co-Leader

Project 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors
Dawn Quelle, PhD, Project Leader, Ben Darbro, MD, PhD, Co-Leader

Project 3: Genetic Studies of IIeal Neuroendocrine Tumors
James Howe, MD, Project Leader, Terry Braun, PhD, Co-Leader

Project 4: New Approaches to Improving the Effectiveness of Radionuclide Targeted Treatments in Neuroendocrine Tumors
David Bushnell, MD, Project Leader, Michael Schultz, PhD, Co-Leader

Figure 1: Anatomical Distribution of Neuroendocrine Tumors

The four cores enhance the infrastructure that is vital to the success of the NET SPORE projects.

Administration
M Sue O’Dorisio, MD, PhD, Director,
James Howe, MD; Co-Director

Biospecimens
Michael Knudson, MD, PhD, Director;
Chuck Lynch, PhD, Co-Director

Clinical Research
Thomas O’Dorisio, MD; Director,
Daniel Vaena, MD; Co-Director,
Terry Braun, PhD, Co-Director

Biostatistics and Bioinformatics
Gideon Zamba, PhD, Co-Director,
Terry Braun, PhD, Co-Director

PROJECT 1: THERANOSTICS IN NEUROENDOCRINE TUMORS

Menda Yusuf, MD, Project Leader
M. Sue O’Dorisio, MD, PhD, Co-Leader
Molly Martin, PhD, Co-Investigator

Neuroendocrine tumors (NETs) constitute an unrecognized health threat to children and adults. The incidence and prevalence of NETs is rising in the United States; yet, there is very little research on NETs, and no effective treatment for patients with metastatic disease, many of whom die within five years of diagnosis according to the latest SEER data. NETs do not respond to conventional chemotherapy or external beam radiation, making development of new diagnostic and therapeutic options imperative. We hypothesize that theranostics, use of a single compound as both a therapeutic and a diagnosticagent, will meet this critical need for children and adults with NETs.

The pre-clinical component of this proposal will identify new theranostic targets on neuroendocrine tumor cells, design and synthesize peptides to hit these new targets, and test the most promising theranostic compounds in vivo. Oxytocin, melanocortin, and glucose-dependent insulinotropic peptide receptors are expressed on neuroendocrine tumors and are prime new targets in neuroendocrine tumors. We will design and synthesize peptides that can bind to each receptor; peptides that demonstrate high affinity and stability in vitro will then be tested as diagnositic PET imaging agents in pre-clinical models of bronchial, small bowel and pancreatic NETs.

The new peptides that meet the strict criteria set by the FDA for PET imaging agents will be brought forward as potential theranostic drugs for patients with NETs. We will apply to the FDA for investigational new drug (IND) to conduct “first in human” PET imaging studies using the best pre-clinical agents. Successful completion of these pre-clinical and “first in human” imaging trials will pave the way for development of new therapeutic radioactive drugs with the ultimate goal of providing new imaging and therapy options for patients with neuroendocrine tumors.

Project 1’s Specific Aims are to:

  1. Design and synthesize unique, high-affinity, stable ligands for use in G-protein coupled receptor (GPCR) targeted theranostics.
  2. Characterize in vivo specificity, stability, pharmacokinetics, and cytotoxicity of new GPCR targeted theranostic compounds in mouse models of NETs.
  3. Examine safety and efficacy of new GPCR targeted PET tracers in humans using exploratory IND.

PROJECT 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors

Dawn Quelle, PhD, Project Leader
Ben Darbro, MD, PhD, Co-Leader

Neuroendocrine tumors (NETs) are slow growing cancers that are increasing in incidence and display profound resistance to conventional therapies. They are a growing clinical challenge. Mechanisms underlying NET development are only partly understood, and biomarkers that could help diagnose the disease or predict patient prognosis are lacking. While progress in managing pancreatic NETs (PNETs) over the past several decades has been slow, some new targeted therapies have emerged as we’ve learned more about molecular mechanisms of PNET pathogenesis. Mounting evidence suggests that drug combinations targeting multiple steps of the tumor-promoting PI3K/Akt/mTOR pathway will reduce NET resistance to therapy and improve patient outcome. However, better understanding of PI3K/Akt/mTOR regulation and identification of PNET biomarkers that risk stratify patients into subgroups of those who will (or will not) respond to particular therapies is needed. This project was developed with those goals in mind. Aim 1 is to define clinically relevant therapeutic targets that control PNET proliferation and survival. It builds upon our discovery that RABL6A (a novel oncoprotein) is essential for PNET cell survival and proliferation, Akt/mTOR activity, and control of other clinically relevant PNET pathways, such as Rb1. Aim 2 is to identify genetic and proteomic biomarkers that discriminate NET type and prognosis. It is based on pilot studies that identified several genetic changes capable of distinguishing pancreatic from ileal NETs (including RABL6A gene amplification), and seeks to define new DNA and protein biomarkers that distinguish four different types of NETs (pancreatic, ileal, bronchial and cervical). The integration of findings from Aims 1 and 2 will establish novel relationships between the status of drug-targetable PNET pathways (RABL6A-Akt/mTOR, RABL6A-Rb1) with genetic alterations that discriminate NET type and prognosis. As such, this research will identify molecular alterations that are common or unique to various types of NETs, as well as primary versus metastatic tumors. The most immediate clinical outcome of this translational project will be the development of fast and inexpensive genetic (FISH-based) and proteomic (IHC-based) tests for differentiating various types of NETs in patients. This should markedly improve NET diagnosis, classification, prognosis and treatment.

PROJECT 3: GENETIC STUDIES OF IIEAL NEUROENDOCRINE TUMORS

James Howe, MD, Project Leader
Terry Braun, PhD, Co-Leader
Andrew Bellizzi, MD, Co-Investigator

The incidence of Neuroendocrine Tumors (NETs) has increased five-fold over the last three decades, and many patients do not develop symptoms until the tumors have metastasized. Further understanding of the molecular biologic basis of NETs holds the promise for improved diagnosis, imaging, and therapy. We will analyze the DNA and gene expression profiles of these tumors to identify important genes that will facilitate clinical advances for patients with these tumors. This contribution will be significant because it will allow us to determine the tumor site of origin in patients presenting with liver metastases and unknown primary tumors, which will lead to more directed surgical exploration and resection; and knowledge of cell surface receptors or other genes significantly over-expressed in NETs relative to normal tissues will facilitate the development of new targets for detection, imaging, and medical management. Novel targets for therapy will also be suggested by the identification of frequently mutated or deleted genes in these tumors or the germline of patients with familial NETs. Pancreatic neuroendocrine tumors have several effective treatments for metastatic tumors, but interestingly small bowel neuroendocrine tumors do not respond to these same therapies. Another outcome of this work will be to understand the molecular basis of both forms of metastatic tumors in order to develop new treatment strategies. We anticipate that changes found at the DNA or RNA level will translate into corresponding changes in protein expression, which is the next step for assessing the potential value of targets identified through these approaches that can then be exploited to develop better clinical testing and therapeutic options for these patients. Few studies have looked for predisposing genes in cases of familial NETs which would be expected to yield valuable new clues into the pathogenesis and management of these tumors.

PROJECT 4: NEW APPROACHES TO IMPROVING THE EFFECTIVENESS OF RADIONUCLIDE TARGETED TREATMENTS IN NEUROENDOCRINE

David Bushnell, MD, Project Leader
Michael Schultz, PhD, Co-Leader
Thomas O’Dorisio, MD, Co-Investigator
Mark Madsen, PhD, Co-Investigator

Neuroendocrine tumors (NETs) are considered an Orphan Disease with a low incidence in the United States. Consequently, it has proven very difficult to secure the interest or resources needed to bring newer treatments to the clinical arena for these patients. Although slow to progress in the early stages, once NETs metastasize, the current 5-year survival rate is <50%. Newer, more effective forms of therapy are urgently needed. Targeted radionuclide therapies using single agents such as 131I-metaiodobenzylguanidine (131I MIBG) and 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) have shown promise for therapy of small bowel NETs with response rates of 20-40%. Unfortunately, complete responses are notably uncommon, occurring in less than 10% of patients and response duration is often disappointing as well. We propose a Phase I clinical trial combining 90Y-DOTATOC and 131I MIBG that should provide an increase in the radiation dose delivered to tumors without exceeding safe limits for normal kidney and bone marrow. This trial design, based on strong preliminary imaging data and radiation dose modeling, has the potential to provide durable therapeutic benefit for patients with small bowel NETs where other therapeutic strategies fall short.

In further basic science studies, we propose an innovative strategy targeting unique G-protein coupled receptor hetero-dimers such as somatostatin receptor/dopamine receptor conjugates that we have identified in NETs. Preliminary data demonstrate that these new targeting agents have high affinity binding to tumor cells; they are predicted to be highly specific for tumor cells as the hetero-dimeric receptors are rarely expressed in normal tissues. Successful development of these unique radionuclide therapies will provide a new paradigm for molecular targeting and image-guided radionuclide therapy that will likely be translated to other malignancies.

Our overarching hypothesis is that multiple targeting approaches conducted simultaneously can lead to increased delivery of radiation dose to NET relative to normal tissues and provide improved durable benefit to patients. We will test this hypothesis through two specific aims:

Aim 1. Establish the maximum tolerated critical organ dose levels of 131I MIBG and 90Y DOTATOC administered in combination to patients with midgut NET.

Aim 2. Design and synthesize multi-receptor targeted ligands for imaging and therapy of NET.

Administration Core

M. Sue O’Dorisio, MD, PhD, Director
James Howe, MD, Co-Director

The Administration Core is the organizational hub for the NET SPORE. Its overall goal is to support translational research in neuroendocrine tumors (NETS) by facilitating scientific interactions between basic and clinical investigators in order to bring new diagnostic and therapeutic options to patients with these rare malignancies. The Administrative Core optimizes the access of investigators to additional resources within the University of Iowa and externally.

Aims for this Core include:

  • provide leadership, organizational support, and financial management to SPORE core directors and to investigators for both major and developmental projects;
  • work with the Executive Committee to provide continual scientific review to select and support the most promising full projects and developmental projects in accordance with SPORE guidelines;
  • foster career development for investigators dedicated to basic and clinical research in NETs;
  • provide oversight of SPORE Cores to ensure continual quality improvement in services for investigators;
  • coordinate monthly investigator meetings, quarterly progress reviews by the internal review committee, and a yearly review by the External review committee;
  • work with investigators and patient advocates to build new internal and external collaborations that will expand access to comprehensive, state-of-the-art care for patients with neuroendocrine tumors;
  • disseminate new information from SPORE investigations to professional and patient organizations who care for patients with neuroendocrine tumors, to the scientific community, and to the public;
  • maintain timely communications with the National Cancer Institute;
  • continually improve Program Organization and Capabilities through excellent communication and collaboration with the Holden Comprehensive Cancer Center (HCCC), the Institute for Clinical and Translational Sciences (ICTS), and the Colleges of Medicine, Engineering, and Public Health.

Biospecimens Core

Andrew Bellizzi, MD, Director
C. Michael Knudson, MD, PhD, Co-Director

The Iowa Neuroendocrine Tumor (NET) SPORE Biospecimens Core provides a coordinated, centralized, and dedicated core for the procurement, processing and annotation of biospecimens from patients in our Iowa Neuroendocrine Tumor Registry and also from Iowa Cancer Registry’s Virtual and Residual Tissue Repositories. The primary goal of the Biospecimens Core is to procure a variety of biologic specimens on patients with neuroendocrine tumors. These specimens will include fresh or rapidly frozen specimens from patients who have signed the Iowa NET Registry consent as well as de-identified, formalin-fixed paraffin-embedded (FFPE) specimens obtained through the Surveillance Epidemiology and End Results (SEER) residual tissue repository (RTR) and the Iowa SEER Virtual Tissue Repository (VTR). All specimens will be tracked and stored under conditions that optimize their utility for molecular studies, assuring the Iowa NET SPORE investigators have access to a large number of a wide variety of NET tumor, normal, and germline specimens. Specific Aims of the Biospecimens Core are: 1) Collect, process, bank and distribute excess surgical specimens and/or blood/buccal swabs from patients and family members who have signed consent to participate in the Iowa NET Registry; 2) Acquire, process, and distribute de-identified neuroendocrine tumor FFPE specimens obtained through the Iowa Virtual Tumor Repository and SEER Residual Tissue Repository; 3) Provide accurate diagnosis and grade on all tumor specimens according to North American Neuroendocrine Tumor Society (NANETS) guidelines; 4) Work with the Biostatistics and Bioinformatics Core to maintain data obtained from Iowa NET Registry biospecimens and SEER Repository biospecimens to further collaborative research leading to improved long term outcomes for patients with NETs.

Clinical Research Core

Tom O’Dorisio, MD, Director
Daniel Vaena, MD, Co-Director
Terry Braun, PhD, Co-Director

The Iowa Neuroendocrine Tumor SPORE Clinical Research Core (CRC) has, as its primary goal, to enable each project to bring the fruit of its scientific research to a clinical end point that will benefit patients both proximally and in the future. The Clinical Research Core is the direct translational link between research projects and clinical research emanating from these projects. The CRC obtains consent from newly diagnosed and referred patients with NETs, abstracts and enters clinical and epidemiologic data into the Neuroendocrine Tumor Database (REDCap), and systematically manages and treats patients through death. Tumor tissue and peripheral blood, serum, cells, DNA, and RNA are prospectively collected, stored and tracked in LabMatrix™ by the Biospecimens Core for linkage to the database. This provides integrated and centralized access to SPORE investigators for NET research projects. The Iowa Neuroendocrine Tumor Clinic and Registry were established by Dr. Tom O’Dorisio in 2000 and over 1300 subjects (and family members) with NETs have been consented to this Registry. Iowa SPORE investigators have been active in design and conduct of both investigator-initiated and NCI cooperative group trials for patients with NETs. These trials have encompassed imaging and dosimetry trials, therapeutic trials of new targeted biologicals and peptide receptor radionuclide therapy (PRRT); and the only Phase I trial of PRRT for children and adolescents. For this research project, the activities of the CRC will be to i) consent and enroll patients into the Iowa Neuroendocrine Tumor Registry and to further develop the Iowa Neuroendocrine Tumor Database, ii) Coordinate and perform SPORE clinical trials protocols providing a critical link between clinical research, projects, cores, and developmental research projects and iii) evaluate the validity of and coordinate incorporation of new genetic, pathologic, and imaging tests, developed by the SPORE research projects, into new clinical trials. Patients with neuroendocrine tumors (NETs) have few opportunities to participate in clinical trials due to the scarcity of NCI sponsored, investigator-initiated or cooperative group trials for these rare malignancies. Industry-supported clinical trials are also limited because this small patient population is not likely to return a large profit. Iowa is one of few centers in the US capable of recruiting sufficient patients to carry out a clinical trial and is the only translational program in the United States that is capable of offering Theranostics utilizing molecularly targeted PET imaging to guide therapy with 90Y-DOTATOC, 177Lu-DOTA-Octreotate, and 131I-MIBG. The Iowa NET SPORE seeks to provide this opportunity to patients through a Clinical Research Core with a robust program of clinical trials encompassing diagnosis, therapy, symptom control, and extended high quality of life.

Biostatistics & Bioinformatics Research Core

Gideon Zamba, PhD, Co-Director
Terry Braun, PhD, Co-Director

The Biostatistics and Bioinformatics Core provides integrative statistical and informatics support to the Iowa Neuroendocrine Tumor (NET) SPORE. The comprehensive nature of the Core encompasses basic, translational, and clinical projects, assuring each SPORE investigator access to expertise that includes development of study designs, state of the art data analysis and interpretation, data management resources, abstract and manuscript preparation, and synergistic interaction with all other core components through analyses and information sharing. The Core builds upon the innovative procedures and systems in the University of Iowa Holden Comprehensive Cancer Center, the Department of Biostatistics in the College of Public Health and the Coordinated Laboratory for Computational Genomics in the School of Engineering. Design and analysis support will be provided across a range of fields, including basic chemistry and pharmacology, exome sequencing and mutation discovery, RNA-sequencing analysis, expression analysis, imaging pharmacokinetics and dosimetry, clinical trials, and population science. The Core will provide data management for clinical trials through the University of Iowa Holden Comprehensive Cancer Center (HCCC) OnCore data management system, monitor adverse events in collaboration with the Clinical Research Core, manage the Iowa Neuroendocrine Registry in REDCap, coordinate Biospecimens data in LabMatrix, and prepare data summaries for manuscript preparation. Support is also provided for the management and integration of existing and newly collected data through consistent and compatible genomic data handling. Additional areas of support for clinical trials include data form development and processing, data collection and entry, data archiving, quality control, and data safety monitoring. In addition to being actively involved with the preparation of statistical plans for the four projects in this application, the Core was also involved in the management of information pertaining to Exome sequencing, gene mutation identification and analysis of G-protein coupled receptor expression.

Career Enhancement Program

James Howe, MD, Director

The Iowa Neuroendocrine Tumor SPORE Career Enhancement Program (CEP) will provide support for integrated training and education to new investigators committed to careers in neuroendocrine tumor translational research. The CEP is designed to provide intense research experience to awardees who require additional research knowledge and skills in order to compete for independent extramural grant support in neuroendocrine tumor translational research.

Developmental Research Program

Douglas Spitz, PhD, Director

The Iowa Neuroendocrine Tumor SPORE Developmental Research Program (DRP) will support innovative, scientifically sound projects that investigate any area pertaining to translational neuroendocrine tumor research. Developmental funding will stimulate research that incorporates innovative techniques and new theoretical approaches that may not have been previously utilized in neuroendocrine tumor research. In so doing it provides a mechanism by which the SPORE can increase the number of scientists and clinical investigators who are committed to translational neuroendocrine tumor research. It will provide guidance from and collaboration with senior investigators, full access to SPORE shared resources, and financial support for early phase research that takes maximum advantage of SPORE resources to generate feasibility data for projects that have the highest translational potential.